Pharmacophore identification of c-Myc inhibitor 10074-G5 |
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| Authors: | Jeremy L Yap Huabo Wang Angela Hu Jay Chauhan Kwan-Young Jung Robert B Gharavi Edward V Prochownik Steven Fletcher |
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| Institution: | 1. Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine St, Baltimore, MD 21201, USA;2. Division of Hematology/Oncology, Children’s Hospital of Pittsburgh, 4401 Penn Ave, Pittsburgh, PA 15224, USA;3. PharmD Program, University of Maryland School of Pharmacy, 20 N Pine St, Baltimore, MD 21201, USA;4. Department of Microbiology and Molecular Genetics, The University of Pittsburgh Medical Center and the University of Pittsburgh Cancer Institute, Pittsburgh, PA 15201, USA;5. University of Maryland Marlene and Stewart Greenebaum Cancer Center, 22 S Greene St, Baltimore, MD 21201, USA |
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| Abstract: | A structure–activity relationship (SAR) study of the c-Myc (Myc) inhibitor 10074-G5 (N-(1,1′-biphenyl]-2-yl)-7-nitrobenzoc]1,2,5]oxadiazol-4-amine, 1) – which targets a hydrophobic domain of the Myc oncoprotein that is flanked by arginine residues – was executed in order to determine its pharmacophore. Whilst the 7-nitrobenzofurazan was found to be critical for inhibitory activity, the ortho-biphenyl could be replaced with a para-carboxyphenyl group to furnish the new inhibitor JY-3-094 (3q). Around five times as potent as the lead with an IC50 of 33 μM for disruption of the Myc–Max heterodimer, JY-3-094 demonstrated excellent selectivity over Max–Max homodimers, with no apparent effect at 100 μM. Importantly, the carboxylic acid of JY-3-094 improves the physicochemical properties of the lead compound, which will facilitate the incorporation of additional hydrophobicity that might enhance Myc inhibitory activity further still. |
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